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PROPERTIES AND USES

PULMONARY TOXICITY OF SINGLE-WALLED NANOTUBES IN MICE Chiu-wing Lam, Ph.D. JSC Toxicology Group, and Wyle Laboratories NASA Johnson Space Center, Houston, TX John T. James, Ph.D. /NASA Richard McCluskey, M.D., Ph.D/NASA Robert L. Hunter, M.D.,Ph.D./UT Med. Ctr. PROPERTIES AND USES.

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PROPERTIES AND USES

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  1. PULMONARY TOXICITY OF SINGLE-WALLED NANOTUBES IN MICEChiu-wing Lam, Ph.D. JSC Toxicology Group, and Wyle Laboratories NASA Johnson Space Center, Houston, TXJohn T. James, Ph.D. /NASA Richard McCluskey, M.D., Ph.D/NASARobert L. Hunter, M.D.,Ph.D./UT Med. Ctr.

  2. PROPERTIES AND USES • SWNTs are structurally rolled-up graphite sheets • ~ 1.5 nm diameter and several microns long • Generally pack tightly and parallel to form ropes or rods • Have highly desirable electrical, mechanical, and thermal properties • Potentially wide applications in electronic, computer, and aerospace industries

  3. SYNTHESIS OF SWNT SWNTs are Commonly Synthesized by: • Carbon arc discharge (Carbon source: graphite) • Laser evaporation (Carbon source: graphite) • Chemical vapor deposition (Carbon source: CO as in HiPco Process) ( All these process require catalytic metals, such as Fe, Ni, and Co; products contain residual metals)

  4. Why Do We Need Toxicity Information? Richard Smalley of Rice Univ. has predicted that hundreds or thousands of tons of NTs could be produced in 5 to 10 years and “in time, millions of tonnes of nanotubes will be produced worldwide every year ” (Ball 2001; ISI 2002). Human exposures will increase NTs are light and could become airborne JSC has a Nanolab that makes carbon nanotubes and workers could potentially be exposed to NT. Toxicity of such an important material is unknown Pouring HiPco-NT between Containers at Rice Facility (Courtesy of Drs. Maynard & Baron, NIOSH)

  5. Results of Air sampling of nanotube particles at Rice, CNI and NASA facilities(Courtesy of Dr. Maynard and Dr. Baron, NIOSH, 2002)

  6. Particle size distribution of a HiPCo sample under agitationcourtesy of Baron et al. of NIOSH (2003)

  7. Fine NT particles can potentially reach the lungs. How can we assess NT toxicity in the lungs ? • Inhalation Exposures • Need to isolate dust of respirable size • Need a large amount of material • Experimentally difficult (aerosol generation and monitoring) • NTP study: comprehensive [2 yrs, 2 doses, Rats and Mice (M&F), all organs] • >$10, 000, 000 • Intratracheal Instillation • Need little material • Relatively easy • Less expensive (we received a total of only $70,000 CDDF for the project) • Allow for comparing several dusts in the same experiment • Disadvantages – General single treatment - not way humans are exposed • -- Uneven distribution of dust in lungs

  8. SWNT PRODUCTS WE STUDIED Raw HiPco NT 27.0% Fe, 0.8% Ni Purified HiPco NT 2.1% Fe Carbolex Electric-arc NT 26% Ni, 5%Y, 0.5% Fe

  9. Need Fine (Respirable) Particle for studying effects in the lungs Large airborne particles cannot reach the pulmonary region

  10. LUNG HISTOPATHOLOGY STUDIES OF MICE INTRATRACHEALY INSTILLED WITH NTs A major manufacturer regards NTs as graphite and recommends to use OSHA exposure limit on graphite (5 mg/m3) for NT. If a 30-g mouse breathe 30 ml/min at 5 mg/m3 of respirable-size NT particles and assuming 40% of the dust deposits in the lung, it will take 17 days to reach a lung burden of 0.5 mg

  11. Lungs from Mice of HD-90d Groups

  12. Carbon Black Quartz Serum Histopathologic Micrographs of Lungs from Mice of the HD-7d Groups Carbolex NT Purified NT Raw NT

  13. Quartz Carbolex NT Carbon Black Histopathologic Micrographs of Lungs from Mice of the HD-90d Groups Raw NT (low m.) Raw NT (high m.) Purified NT

  14. Lung Micrographs from Mice of the HD-7d and HD-90d Groups 7d 90d Carbolex NT Raw NT (low m. Purified NT ) Raw NT (hi m.)

  15. Science11 April 2003 issue, p. 243 AMERICAN CHEMICAL SOCIETY MEETING Nanomaterials Show Signs of Toxicity Robert F. Service “… the nanotubes--with or without metal particles--triggered the formation of granulomas, a combination of dead and live tissue surrounding the material that's a significant sign of toxicity, Lam says. Warheit (Du Pont) reported seeing granuloma formation in a similar study but noted that the inflammation seemed to tail off after 3 months…” DuPont - Warheit study used a laser-evaporated NTs in rats NASA Study used HiPco and Carbon arc NTs in mice

  16. SWNT and Carbon Blackare carbon, but Why did SWNT, but not carbon black, produce granulomas ?

  17. SWNTs vs. Carbon Black Individual tube: ~ 1.5 nm diameter and several microns long Bundles: NTs pack tightly and parallel to form ropes or rods Structurally: Individual tubes or bundles are fibers, CB is amorphous Surface chemistry of SWNTs and CB are also different

  18. Why Do We Concern About Granulomas and Fibers? Granulomas (miscropic nodules), consisting particles, live and dead cells, and debris and could impair cellular and physiological (gas exchange) lung functions and give rise to fibrosis, more defined nodules, and other lesions. Fibers are generally of more health hazard than other forms of particulates. It is well established that the pathogenicity of a fiber in the lungs directly correlates with its biopersistency (Oberdorster 2000). NTs are totally insoluble and probably one of the most biologically nondegradable man-made materials. Determining how the NT-induced granulomas progress would require a longer-duration study with this biopersistent material.

  19. CONCLUSIONS ………….. • Granulomas were observed in lungs 7 d or 90 d after an instillation of 0.5 mg NT per mouse (also in some with 0.1 mg); • NT, regardless synthetic methods, types and amounts of residual catalytic metals, produced granulomas; • Lung lesions in the 90-d NT groups, in most cases, more pronounced than those in the 7-d groups.

  20. CONCLUSIONS • Our study shows that, on an equal-weight basis, if carbon nanotubes reach the lungs, they are much more toxic than carbon black and can be more toxic than quartz, which is considered a serious occupational health hazard in chronic inhalation exposures. • If fine NT dusts are present in a work environment, exposure protection strategies should be implemented to minimize human exposures.

  21. ACKNOWLEDGEMENTSThe NT Toxicity study investigators gratefully thank: FUNDING: JSC CDD Fund; JSC Toxicology misc. fund MATERIALS: CNST of Rice U. and Carbolex Inc. PROJECT INITIATION: Ms. A. Lee, Dr. D. Colbert, Dr. R. Hauge STUDY CONTRIBUTION: Dr. M. Kuo, Dr.T. Blasdel, S. Bassett, M. Nelman, J. Nelle, B. Whitaker, and N. Hudson. CONTRUCTIVE COMMENTS: Staff at Rice CNST ACADEMIC SUPPORTS: Dr. V. Colvin and her colleagues

  22. STUDY PRIMARILY OF RESPIRABLE-SIZE PARTICLES PROBABLE OF LITTLE NANOPARTICLES • Rice “aggressive sonication” prepared fine-particle suspensions (10 mg/L) containing mostly individual fibers and a few small bundles. • Our brief sonicated suspension were 200 to 1000x more concentrated and contained particle aggregates. • The high NT concentration and brief sonication minimized deaggregation of NT samples to individual fibers. • Dr. Robert Hauge of Rice U advised us that brief sonication would not shorten or change the fundamental nature of SWNTs.

  23. Environmental Fate of Nanomaterials ??? • 1) Nanomaterials in Soil • Biopersistency • Disolution • Biodegradation • Aggregation (adsorption to environmental matrix) • 2) Nanomaterials in aquatic environment • Dissolution and suspension in aqueous media • Sedimentation • 3) Bioaccumulation Earth worms and Aquatic animals

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